Abstract
Background
The APOE gene has long been associated with Alzheimer Disease (AD) risk. Emerging research indicates that other genetic loci, including the paired immunoglobulin-like type 2 receptor alpha (PILRA) gene, may play a crucial role. In the current study we used UK Biobank data to assess the relationship between PILRA and AD.
Methods
We examined the PILRA polymorphism rs1859788, a single nucleotide missense variant, G > A, minor allele frequency 0.3. Single nucleotide polymorphism (SNP) data for rs429358 and rs7412 determined APOE isoform. We used PheWeb to perform a phenome wide association study (phewas) of rs1859788 and identify other conditions that might be related to both AD and rs1859788.
Results
In male subjects homozygous for ApoE isoform ε4/ε4, of the men without AD, 9.7% had AA genotype; of the men with AD, 1.8% had AA genotype. This difference was significant (p = 0.006, two tail Fisher exact test). In female subjects homozygous for ApoE isoform ε4/ε4, of the women without AD, 10.4% had AA genotype; of the women with AD 7.9% had AA genotype. This difference was not significant (p = 0.481). In subjects not homozygous for ApoE isoform ε4/ε4, the effect of PILRA genotype was not significant. A phewas of rs1859788 found an association with megaloblastic anemia.
Conclusion
We have confirmed the previously noted PILRA snp rs1859788 risk reduction of AD, as well as a PILRA link to the ApoE ε4 isoform that has been previously described. We are uncertain why the significant association is only with men who are homozygous for the ε4/ε4 isoform. A phewas indicated that PILRA SNP rs1859788 is associated with megaloblastic anemia, which may explain an observed association between AD and anemia. The identification of PILRA as a potential risk gene for Alzheimer's disease underscores the complexity of the genetic landscape contributing to AD. Alongside APOE, PILRA may play a significant role in modulating key pathological processes such as neuroinflammation and amyloid-beta accumulation.